Plasma GIP concentrations in nondiabetic and diabetic subjects have been used as an index of secretion of GIP by a variety of investigators. For the interpretation of changes in hormone concentration relative to changes in hormone secretion clearance rates must be known. As a continuation of our efforts to delineate GIP physiology and pathophysiology we will examine GIP clearance rates in lean and obese nondiabetic and diabetic subjects. We will test the hypothesis that GIP clearance differs among these conditions. In addition, clearance rates of GIP will be determined during hyperglycemic glucose clamps to test the hypothesis that the blunted GIP responses during hyperglycemic in healthy subjects purported to be due to insulin inhibition of GIP secretion is due to accelerated GIP clearance. Dose response relationships between GIP and meal size will be determined to test the hypothesis that such relationships differ between lean and obese healthy subjects, thereby explaining much or the conflicting data in the literature regarding differences in GIP responses between these two states. Since GIP may not account for the full incretin effect the hypothesis will be tested that there are other potential incretins besides GIP. Neurotensin, pancreatic polypeptide, glycentin and PHI's effect on insulin secretion will be examined in healthy subjects by the infusion of glucose with and without the incretin candidate at rates to reproduce plasma concentrations of glucose and the incretin observed following oral glucose. Should any of the candidates be found to have incretin activity studies of combined infusions of GIP and that incretin will be conducted to test the hypothesis that the candidate and GIP have synergistic effects thus accounting for the failure of any single incretin to fully express the incretin effect. The presence of hepatocyte GIP and VIP receptors, the extraction of these hormones by the liver, in vitro evidence of biologic effect and the existence of a portal: peripheral venous gradient all suggest that gastrointestinal hormones may modulate hepatic response to a meal. To test this hypothesis rates of glucose turnover (isotopically determined) will be performed in healthy subjects with and without the infusion of the gut hormone (during simultaneous infusions of somatostatin and replacement infusions of insulin and glucagon to ensure equivalent insulin and glucagon concentrations under each experimental condition) during and following the ingestion of an oral glucose load. In addition the insulin dose relationships for suppression of endogenous glucose production in man (using the euglycemic glucose clamps) will be measured.